Background Rates of Adverse Pregnancy Outcomes for Assessing the Safety of Maternal Vaccine Trials in Sub-Saharan Africa

BackgroundMaternal immunization has gained traction as a strategy to diminish maternal and young infant mortality attributable to infectious diseases. Background rates of adverse pregnancy outcomes are crucial to interpret results of clinical trials in Sub-Saharan Africa. MethodsWe developed a mathematical model that calculates a clinical trial's expected number of neonatal and maternal deaths at an interim safety assessment based on the person-time observed during different risk windows. This model was compared to crude multiplication of the maternal mortality ratio and neonatal mortality rate by the number of live births. Systematic reviews of severe acute maternal morbidity (SAMM), low birth weight (LBW), prematurity, and major congenital malformations (MCM) in Sub-Saharan African countries were also performed. FindingsAccounting for the person-time observed during different risk periods yields lower, more conservative estimates of expected maternal and neonatal deaths, particularly at an interim safety evaluation soon after a large number of deliveries. Median incidence of SAMM in 16 reports was 40.7 (IQR: 10.6–73.3) per 1,000 total births, and the most common causes were hemorrhage (34%), dystocia (22%), and severe hypertensive disorders of pregnancy (22%). Proportions of liveborn infants who were LBW (median 13.3%, IQR: 9.9–16.4) or premature (median 15.4%, IQR: 10.6–19.1) were similar across geographic region, study design, and institutional setting. The median incidence of MCM per 1,000 live births was 14.4 (IQR: 5.5–17.6), with the musculoskeletal system comprising 30%. InterpretationSome clinical trials assessing whether maternal immunization can improve pregnancy and young infant outcomes in the developing world have made ethics-based decisions not to use a pure placebo control. Consequently, reliable background rates of adverse pregnancy outcomes are necessary to distinguish between vaccine benefits and safety concerns. Local studies that quantify population-based background rates of adverse pregnancy outcomes will improve safety assessment of interventions during pregnancy.研究背景：母体免疫作为降低感染性疾病所致孕产妇与婴幼儿死亡的有效策略，正受到越来越多的关注。在撒哈拉以南非洲地区，不良妊娠结局的基线率是解读当地临床试验结果的核心依据。 研究方法：本研究开发了一款数学模型，可基于不同风险窗口期内观察到的人时数据，计算临床试验中期安全性评估阶段预计发生的新生儿与孕产妇死亡例数。我们将该模型与直接将孕产妇死亡率比值、新生儿死亡率乘以活产总数的粗乘法计算方法进行了对比。此外，我们还针对撒哈拉以南非洲国家的严重急性孕产妇不良事件（severe acute maternal morbidity, SAMM）、低出生体重儿（low birth weight, LBW）、早产以及重大先天性畸形（major congenital malformations, MCM）开展了系统综述。 研究结果：相较于粗乘法，基于不同风险期观察到的人时数据计算得出的预计孕产妇与新生儿死亡例数更低，结果更为保守，这一差异在大量分娩后不久开展的中期安全性评估中尤为显著。纳入16篇报告的分析显示，严重急性孕产妇不良事件的中位发生率为40.7（四分位距：10.6~73.3）例/每1000活产，最常见的病因为出血（34%）、难产（22%）以及重度妊娠高血压疾病（22%）。不同地理区域、研究设计与机构场景下，活产儿中低出生体重儿（中位占比13.3%，四分位距：9.9~16.4）与早产儿（中位占比15.4%，四分位距：10.6~19.1）的比例无明显差异。每1000活产儿的重大先天性畸形中位发生率为14.4（四分位距：5.5~17.6），其中肌肉骨骼系统畸形占比达30%。 研究启示：部分旨在评估母体免疫能否改善发展中国家妊娠结局与婴幼儿预后的临床试验，已基于伦理考量做出不采用纯安慰剂对照的决策。因此，获取可靠的不良妊娠结局基线率，对于区分疫苗的获益与安全性风险至关重要。针对不良妊娠结局开展基于人群的基线率量化研究，将有助于优化妊娠期间干预措施的安全性评估。